Article (Scientific journals)
The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by a-PD-L1 or a-IL6 antibodies
Rolvering, Catherine; Zimmer, Andreas David; Ginolhac, Aurélien et al.
2018In Journal of Leukocyte Biology, 104, p. 969-985
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Keywords :
cytokine; interferon; IFN-𝛾; IDO-1; OSM
Abstract :
[en] Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells.We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN-𝛾-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-𝛾, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associatedwith immune escape of cancer. Interestingly, differential expression of these geneswas observed within the different cell lines and when comparing IL27 to IFN-𝛾. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other TH1 cytokines were also enhanced or restored upon administration of anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine prestimulation— mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation–induced cachexia—can be antagonized by antibodies against IL6-type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27with blocking antibodies against PD-L1 or/and IL6-type cytokines.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rolvering, Catherine ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Zimmer, Andreas David ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Ginolhac, Aurélien  ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Margue, Christiane  ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Kirchmeyer, Mélanie ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Servais, Florence ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Hermanns, Heike M.;  University Hospital Würzburg > Medical Clinic and Policlinic II, Division of Hepatology
Hergovits, Sabine;  University Hospital Würzburg > Medical Clinic and Policlinic II, Division of Hepatology
Nazarov, Petr V.;  Luxembourg Institute of Health - LIH > Department of Oncology, Proteome and Genome Research Unit
Nicot, Nathalie;  Luxembourg Institute of Health - LIH > Department of Oncology, Proteome and Genome Research Unit
Kreis, Stephanie ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Haan, Serge ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Behrmann, Iris ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Haan, Claude ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
More authors (4 more) Less
External co-authors :
yes
Language :
English
Title :
The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by a-PD-L1 or a-IL6 antibodies
Publication date :
2018
Journal title :
Journal of Leukocyte Biology
ISSN :
0741-5400
Publisher :
Federation of American Societies for Experimental Biology, New York, United States - New York
Volume :
104
Pages :
969-985
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR3975937 - Inflammatory Micrornas In Liver Cancer, 2012 (01/09/2013-31/08/2016) - Iris Behrmann
Funders :
University of Luxembourg Grants
Deutsche Forschungs Gemeinschaft
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